Dataset Information

Safety and Efficacy of Once-Daily Prolonged-Release Tacrolimus in Living Donor Liver Transplantation: An Open-Label, Prospective, Single-Arm, Phase 4 Study.

ABSTRACT: BACKGROUND After liver transplantation (LT), nonadherence to immunosuppressants due to the complex regimen can lead to graft rejection and loss. This study assessed the efficacy and safety of conversion from twice-daily tacrolimus (Bid-Tac) to once-daily prolonged-release tacrolimus (OD-Tac) in living donor LT (LDLT) recipients. MATERIAL AND METHODS Among patients who underwent LDLT between November 2015 and October 2016, those who agreed to participate in this study were screened, and those with good general condition and stable liver functions were enrolled. Participants underwent a conversion from Bid-Tac to OD-Tac with a dose ratio of 1: 1 at about 10-14 weeks after LDLT and were followed-up for 24 weeks. RESULTS Thirty-one patients were enrolled. The median number of conversion days after LDLT was 12.3 weeks (range, 10.3-13.8). Adherence was evaluated during the outpatient visits at weeks 2, 4, 8, 16, and 24 after Tac conversion, and 100% adherence was observed at all time points. There were no cases of acute rejection, graft loss, or patient death after Tac conversion. Nineteen cases of adverse events occurred in 11 patients (35.5%), none of which were severe. Alopecia was the most common, affecting 3 (9.7%) patients, followed by pruritus (n=2, 6.45%). There were no changes in renal function or in liver function test, serum glucose level, and lipid profile. CONCLUSIONS Early Tac conversion from Bid-Tac to OD-Tac is safe and feasible. However, further studies are needed to elucidate its long-term effects.

SUBMITTER: Lee EC

PROVIDER: S-EPMC6248274 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Safety and Efficacy of Once-Daily Prolonged-Release Tacrolimus in Living Donor Liver Transplantation: An Open-Label, Prospective, Single-Arm, Phase 4 Study.

Lee Eung Chang EC Kim Seong Hoon SH Park Sang-Jae SJ

Annals of transplantation 20181012

BACKGROUND After liver transplantation (LT), nonadherence to immunosuppressants due to the complex regimen can lead to graft rejection and loss. This study assessed the efficacy and safety of conversion from twice-daily tacrolimus (Bid-Tac) to once-daily prolonged-release tacrolimus (OD-Tac) in living donor LT (LDLT) recipients. MATERIAL AND METHODS Among patients who underwent LDLT between November 2015 and October 2016, those who agreed to participate in this study were screened, and those wit ...[more]

PMID: 30310047

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Project description:INTRODUCTION:Different prolonged-release formulations of tacrolimus are available. To date, the pharmacokinetic (PK) profile of LCP-tacrolimus (LCPT; Envarsus®) has not been compared with PR-Tac (Advagraf®) in de novo kidney transplant recipients. These profiles will guide clinical recommendations for the initiation and dose titration strategies of once-daily tacrolimus formulations. METHODS:This randomized, parallel-group, open-label, multicenter PK study randomized 75 de novo, adult, white kidney transplant recipients to LCPT 0.17 mg/kg/day (n = 37) or PR-Tac 0.20 mg/kg/day (n = 38) for 4 weeks. Dose adjustments were permitted to target a pre-defined therapeutic range based on measured trough blood concentrations. RESULTS:PK analysis (days 1, 3, 7 and 14) included 68 patients (LCPT, n = 33; PR-Tac, n = 35). Similar proportions of patients were within the pre-defined therapeutic tacrolimus trough blood concentration range, with < 12% in each group having below-target trough levels over the study period. LCPT demonstrated ~ 30% greater relative bioavailability [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 1.32 (p = 0.007); day 7, 1.25 (p = 0.051); day 14, 1.43 (p = 0.002)] and ~ 30% lower peak-to-trough percentage fluctuation of blood concentration [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 0.70 (p < 0.001); day 7, 0.68 (p < 0.001); day 14, 0.73 (p = 0.004)] in addition to longer time to maximum blood concentration (tmax), lower maximum concentration (Cmax) and a consistently lower daily dose (~ 40% dose reduction with LCPT vs. PR-Tac by day 28). Safety profiles were similar. CONCLUSION:In de novo kidney transplant recipients, prolonged-release formulations of tacrolimus can reach therapeutic concentrations in the immediate post-transplant period. LCPT has greater relative bioavailability and lower peak-to-trough fluctuation compared with PR-Tac. TRIAL REGISTRATION:Registered at ClinicalTrials.gov; study number NCT02500212. FUNDING:Chiesi Farmaceutici S.p.A.

Project description:Twice daily TAC (BID TAC) and prolonged released once daily dose tacrolimus (OD TAC) have different pharmacokinetic (PK) profiles in kidney transplant (KT) recipients. Precise dose adjustment recommendations when converting from BID TAC to OD TAC remain inconclusive. A single center, PK study was conducted in stable KT recipients taking constant doses of TAC, mycophenolic acid, and prednisolone. The area under the concentration-time curve (AUC) 0-24 and Ctrough were measured before and 4 weeks after 1:1 conversion from BID TAC to OD TAC without subsequent dose adjustment. A 90% confidence interval (CI) of geometric mean ratio (GMR) of OD TAC/BID TAC within the range of 0.9-1.11 was utilized to indicate equivalence of the narrow therapeutic index drugs. The roles of CYP3A5 genotypic polymorphism on PK parameters were also assessed. There were 20 patients with median time since transplantation of 18 months. The mean of CKD-EPI eGFR was 60.7 ± 16.43 mL/min/1.73 m2. The median total daily TAC dose of 0.058 mg/kg/day. The geometric means (%CV) of AUC0-24 of OD and BID TAC were 205.16 (36.4%) and 210.3 (32.5%) ng/mL × h, respectively, with a GMR of 0.98 (90%CI 0.91-1.04). The geometric means (%CV) of Ctrough of OD TAC and BID TAC were 5.43 (33.1%) and 6.09 (34.6%) ng/mL, respectively. The GMR of Ctrough was 0.89 (90%CI 0.82-0.98), which was below 0.9. The newly calculated target Ctrough level of OD TAC was 4.8-6.2 ng/mL. The best abbreviated AUC0-24 was AUC = 0.97(C0) + 5.79(C6) + 18.97(C12) - 4.26. The GMR AUC0-24 was within the range of 0.9-1.11 irrespective of CYP3A5 genotypic polymorphism while the GMR of Ctrough was below 0.9 only in the CYP3A5 expressor patients. The 1:1 conversion from BID TAC to OD TAC without subsequent dose adjustment provided similar AUC0-24 regardless of CYP3A5 genotypic polymorphism. However, the Ctrough was lower in the CYP3A5 expressor group. Therefore, it is not necessary to routinely increase the OD TAC dose after conversion.Trial registration: Thai Clinical Trials Registry (TCTR20210715002).

Dataset Information

Safety and Efficacy of Once-Daily Prolonged-Release Tacrolimus in Living Donor Liver Transplantation: An Open-Label, Prospective, Single-Arm, Phase 4 Study.

Publications

Safety and Efficacy of Once-Daily Prolonged-Release Tacrolimus in Living Donor Liver Transplantation: An Open-Label, Prospective, Single-Arm, Phase 4 Study.

Similar Datasets

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